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  • Zyxin ( ZYX ) promotes invasion and acts as a biomarker for aggressive phenotypes of human glioblastoma multiforme
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-16
    Xian-Mei Wen; Tao Luo; Yi Jiang; Li-Hong Wang; Ying Luo; Qian Chen; Kaidi Yang; Ye Yuan; Chunhua Luo; Xiang Zhang; Ze-Xuan Yan; Wen-Juan Fu; Yu-Huan Tan; Qin Niu; Jing-Fang Xiao; Lu Chen; Jiao Wang; Jia-Feng Huang; You-Hong Cui; Xia Zhang; Yan Wang; Xiu-Wu Bian
    更新日期:2020-01-16
  • Correction: OxHDL controls LOX-1 expression and plasma membrane localization through a mechanism dependent on NOX/ROS/NF-κB pathway on endothelial cells
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-15
    Lorena Pérez; Alejandro Vallejos; Cesar Echeverria; Diego Varela; Claudio Cabello-Verrugio; Felipe Simon
    更新日期:2020-01-15
  • Correction: The high-density lipoprotein receptor Scarb1 is required for normal bone differentiation in vivo and in vitro
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-15
    Irina L. Tourkova; Steven F. Dobrowolski; Cassandra Secunda; Mone Zaidi; Ioanna Papadimitriou-Olivgeri; Dionysios J. Papachristou; Harry C. Blair

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-01-15
  • Correction to: Knockout of α-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-14
    Ying Wan; Ludovica Ceci; Nan Wu; Tianhao Zhou; Lixian Chen; Julie Venter; Heather Francis; Francesca Bernuzzi; Pietro Invernizzi; Konstantina Kyritsi; Paul Baker; Qiaobing Huang; Chaodong Wu; Amelia Sybenga; Gianfranco Alpini; Fanyin Meng; Shannon Glaser

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-01-14
  • TGFβ1-Smad canonical and -Erk noncanonical pathways participate in interleukin-17-induced epithelial–mesenchymal transition in Sjögren’s syndrome
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-10
    Margherita Sisto; Loredana Lorusso; Giuseppe Ingravallo; Domenico Ribatti; Sabrina Lisi
    更新日期:2020-01-10
  • Knockdown of sodium channel Na x reduces dermatitis symptoms in rabbit skin
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-10
    Jingling Zhao; Shengxian Jia; Ping Xie; Emily Friedrich; Robert D. Galiano; Shaohai Qi; Renxiang Mao; Thomas A. Mustoe; Seok Jong Hong
    更新日期:2020-01-10
  • Role of cyclin-dependent kinase 2 in the progression of mouse juvenile cystic kidney disease
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-08
    Jennifer Qin Jing Zhang; Jane Burgess; Daria Stepanova; Sayanthooran Saravanabavan; Annette T. Y. Wong; Philipp Kaldis; Gopala K. Rangan
    更新日期:2020-01-09
  • RAMP1 signaling in immune cells regulates inflammation-associated lymphangiogenesis
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-07
    Seri Tsuru; Yoshiya Ito; Hiromi Matsuda; Kanako Hosono; Tomoyoshi Inoue; Shuji Nakamoto; Chie Kurashige; Toshiaki Mishima; Kazutake Tsujikawa; Hirotsugu Okamoto; Masataka Majima
    更新日期:2020-01-07
  • Correction: Extra-mitochondrial citrate synthase initiates calcium oscillation and suppresses age-dependent sperm dysfunction
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-06
    Woojin Kang; Yuichirou Harada; Kenji Yamatoya; Natsuko Kawano; Seiya Kanai; Yoshitaka Miyamoto; Akihiro Nakamura; Mami Miyado; Yoshiki Hayashi; Yoko Kuroki; Hidekazu Saito; Yasuhiro Iwao; Akihiro Umezawa; Kenji Miyado

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-01-06
  • Accelerated instability testing reveals quantitative mass spectrometry overcomes specimen storage limitations associated with PD-L1 immunohistochemistry
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-02
    Alexander Haragan; Daniel C. Liebler; Dimple M. Das; Michael D. Soper; Ryan D. Morrison; Robbert J. C. Slebos; Bradley L. Ackermann; Jeff A. Fill; Andrew E. Schade; John R. Gosney; Aaron M. Gruver
    更新日期:2020-01-04
  • 更新日期:2020-01-04
  • Macrophage-derived neurotrophin-3 promotes heterotopic ossification in rats
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-02
    Jie Zhang; Liang Wang; Jun Chu; Xiang Ao; Tao Jiang; Bin Yan; Minjun Huang; Zhongmin Zhang
    更新日期:2020-01-04
  • Production of TRPV2-targeting functional antibody ameliorating dilated cardiomyopathy and muscular dystrophy in animal models
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-02
    Yuko Iwata; Shigeo Wakabayashi; Shin Ito; Masafumi Kitakaze
    更新日期:2020-01-04
  • Regulation of pancreatic cancer TRAIL resistance by protein O -GlcNAcylation
    Lab. Invest. (IF 3.684) Pub Date : 2020-01-02
    Shan-zhong Yang; Fei Xu; Kaiyu Yuan; Yong Sun; Tong Zhou; Xinyang Zhao; Jay M. McDonald; Yabing Chen
    更新日期:2020-01-02
  • TRPV2 channel as a possible drug target for the treatment of heart failure
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Yuko Iwata; Shin Ito; Shigeo Wakabayashi; Masafumi Kitakaze
    更新日期:2019-12-20
  • Mechanism for the lethal effect of enterovirus A71 intracerebral injection in neonatal mice
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Min Feng; Yun Liao; Yang Gao; Guorun Jiang; Lichun Wang; Ying Zhang; Shengtao Fan; Xingli Xu; Qihan Li
    更新日期:2019-12-20
  • Development of multiple features of antigen-induced asthma pathology in a new strain of mast cell deficient BALB/c- Kit W-sh/W-sh mice
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Joseph D. Hernandez; Mang Yu; Riccardo Sibilano; Mindy Tsai; Stephen J. Galli
    更新日期:2019-12-20
  • S100A4/non-muscle myosin II signaling regulates epithelial-mesenchymal transition and stemness in uterine carcinosarcoma
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Masataka Tochimoto; Yasuko Oguri; Miki Hashimura; Ryo Konno; Toshihide Matsumoto; Ako Yokoi; Yoshio Kodera; Makoto Saegusa
    更新日期:2019-12-20
  • Castration-induced stromal remodeling disrupts the reconstituted prostate epithelial structure
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Shinya Kajiwara; Kenichiro Ishii; Takeshi Sasaki; Manabu Kato; Kohei Nishikawa; Hideki Kanda; Kiminobu Arima; Masatoshi Watanabe; Yoshiki Sugimura
    更新日期:2019-12-20
  • The TRPV4-AKT axis promotes oral squamous cell carcinoma cell proliferation via CaMKII activation
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Shinsuke Fujii; Yudai Tajiri; Kana Hasegawa; Shinji Matsumoto; Reiko U. Yoshimoto; Hiroko Wada; Shosei Kishida; Mizuho A. Kido; Hiromasa Yoshikawa; Satoru Ozeki; Tamotsu Kiyoshima
    更新日期:2019-12-20
  • Extra-mitochondrial citrate synthase initiates calcium oscillation and suppresses age-dependent sperm dysfunction
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Woojin Kang; Yuichirou Harada; Kenji Yamatoya; Natsuko Kawano; Seiya Kanai; Yoshitaka Miyamoto; Akihiro Nakamura; Mami Miyado; Yoshiki Hayashi; Yoko Kuroki; Hidekazu Saito; Yasuhiro Iwao; Akihiro Umezawa; Kenji Miyado
    更新日期:2019-12-20
  • Adipophilin expression in cutaneous malignant melanoma is associated with high proliferation and poor clinical prognosis
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Masakazu Fujimoto; Ibu Matsuzaki; Kazuchika Nishitsuji; Yuki Yamamoto; Daisuke Murakami; Takanori Yoshikawa; Ayaka Fukui; Yuuki Mori; Masaru Nishino; Yuichi Takahashi; Yoshifumi Iwahashi; Kenji Warigaya; Fumiyoshi Kojima; Masatoshi Jinnin; Shin-ichi Murata
    更新日期:2019-12-20
  • Immunomodulator polyinosinic-polycytidylic acid enhances the inhibitory effect of 13- cis -retinoic acid on neuroblastoma through a TLR3-related immunogenic-apoptotic response
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Hui-Ching Chuang; Hung-Yu Lin; Pei-Lin Liao; Chao-Cheng Huang; Li-Ling Lin; Wen-Ming Hsu; Jiin-Haur Chuang
    更新日期:2019-12-20
  • Mitochondrial dysfunction/NLRP3 inflammasome axis contributes to angiotensin II-induced skeletal muscle wasting via PPAR-γ
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-19
    Yuqing Liu; Xiao Bi; Yumei Zhang; Yingdeng Wang; Wei Ding
    更新日期:2019-12-19
  • Inside the USCAP Journals
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-17
    Alexander Lazar
    更新日期:2019-12-18
  • TRPC5 regulates axonal outgrowth in developing retinal ganglion cells
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-16
    Mai Oda; Hanako Yamamoto; Hidetaka Matsumoto; Yasuki Ishizaki; Koji Shibasaki
    更新日期:2019-12-17
  • Transient receptor potential cation channel subfamily V and breast cancer
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-10
    Choon Leng So, Michael J. G. Milevskiy, Gregory R. Monteith
    更新日期:2019-12-11
  • Arctigenin alleviates myocardial infarction injury through inhibition of the NFAT5-related inflammatory phenotype of cardiac macrophages/monocytes in mice
    Lab. Invest. (IF 3.684) Pub Date : 2019-12-02
    Shi-Hao Ni, Shu-Ning Sun, Zheng Zhou, Yue Li, Yu-Sheng Huang, Huan Li, Jia-Jia Wang, Wei Xiao, Shao-Xiang Xian, Zhong-Qi Yang, Ling-Jun Wang, Lu Lu
    更新日期:2019-12-02
  • SOX2 has dual functions as a regulator in the progression of neuroendocrine prostate cancer
    Lab. Invest. (IF 3.684) Pub Date : 2019-11-26
    Haiying Li, Lili Wang, Zhang Li, Xu Geng, Ming Li, Qi Tang, Chunxiao Wu, Zhiming Lu
    更新日期:2019-11-27
  • Establishment of a Gorlin syndrome model from induced neural progenitor cells exhibiting constitutive GLI1 expression and high sensitivity to inhibition by smoothened (SMO)
    Lab. Invest. (IF 3.684) Pub Date : 2019-11-22
    Hajime Ikehara, Katsunori Fujii, Toshiyuki Miyashita, Yu Ikemoto, Marina Nagamine, Naoki Shimojo, Akihiro Umezawa
    更新日期:2019-11-22
  • CCL8 secreted by tumor-associated macrophages promotes invasion and stemness of glioblastoma cells via ERK1/2 signaling
    Lab. Invest. (IF 3.684) Pub Date : 2019-11-20
    Xiang Zhang, Lu Chen, Wei-qi Dang, Mian-fu Cao, Jing-fang Xiao, Sheng-qing Lv, Wen-jie Jiang, Xiao-hong Yao, Hui-min Lu, Jing-ya Miao, Yan Wang, Shi-cang Yu, Yi-fang Ping, Xin-dong Liu, You-hong Cui, Xia Zhang, Xiu-wu Bian
    更新日期:2019-11-21
  • Inside the USCAP Journals
    Lab. Invest. (IF 3.684) Pub Date : 2019-11-20
    Alexander Lazar
    更新日期:2019-11-21
  • Maternal diet intervention before pregnancy primes offspring lipid metabolism in liver
    Lab. Invest. (IF 3.684) Pub Date : 2019-11-20
    Yi Zhou, Hui Peng, Huiting Xu, Jiangyuan Li, Mikhail Golovko, Henghui Cheng, Ernest C. Lynch, Lin Liu, Naomi McCauley, Lindsey Kennedy, Gianfranco Alpini, Ke K. Zhang, Linglin Xie
    更新日期:2019-11-21
  • Vascular endothelial growth factor enhances profibrotic activities through modulation of calcium homeostasis in human atrial fibroblasts
    Lab. Invest. (IF 3.684) Pub Date : 2019-11-20
    Cheng-Chih Chung, Yung-Kuo Lin, Yao-Chang Chen, Yu-Hsun Kao, Ting-I Lee, Yi-Jen Chen
    更新日期:2019-11-20
  • STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease
    Lab. Invest. (IF 3.684) Pub Date : 2019-11-19
    Xiaoxiao Wang, Huiying Rao, Jingmin Zhao, Aileen Wee, Xiaohe Li, Ran Fei, Rui Huang, Chaodong Wu, Feng Liu, Lai Wei
    更新日期:2019-11-20
  • Inside the USCAP Journals
    Lab. Invest. (IF 3.684) Pub Date : 2019-07-23
    更新日期:2019-11-18
  • TERT assists GDF11 to rejuvenate senescent VEGFR2 + /CD133 + cells in elderly patients with myocardial infarction
    Lab. Invest. (IF 3.684) Pub Date : 2019-07-10
    Lan Zhao, Shaoheng Zhang, Jin Cui, Weiguang Huang, Jiahong Wang, Feng Su, Nannan Chen, Qunlin Gong
    更新日期:2019-11-18
  • Achaete-scute homolog-1 linked to remodeling and preneoplasia of pulmonary epithelium.
    Lab. Invest. (IF 3.684) Pub Date : 2007-05-18
    Xiao-Yang Wang,El Habib Dakir,Xu Naizhen,Sandra M Jensen-Taubman,Francesco J DeMayo,R Ilona Linnoila

    The basic helix-loop-helix protein achaete-scute homolog-1 (ASH1) is involved in lung neuroendocrine (NE) differentiation and tumor promotion in SV40 transgenic mice. Constitutive expression of human ASH-1 (hASH1) in mouse lung results in hyperplasia and remodeling that mimics bronchiolization of alveoli (BOA), a potentially premalignant lesion of human lung carcinomas. We now show that this is due to sustained cellular proliferation in terminal bronchioles and resistance to apoptosis. Throughout the airway epithelium the expression of anti-apoptotic Bcl-2 and c-Myb was increased and Akt/mTOR pathway activated. Moreover, the expression of matrix metalloproteases (MMPs) including MMP7 was specifically enhanced at the bronchiolo-alveolar duct junction and BOA suggesting that MMPs play a key role in this microenvironment during remodeling. We also detected MMP7 in 70% of human BOA lesions. Knockdown of hASH1 gene in human lung cancer cells in vitro suppressed growth by increasing apoptosis. We also show that forced expression of hASH1 in immortalized human bronchial epithelial cells decreases apoptosis. We conclude that the impact of hASH1 is not limited to cells with NE phenotype. Rather, constitutive expression of hASH1 in lung epithelium promotes remodeling through multiple pathways that are commonly activated during lung carcinogenesis. The collective results suggest a novel model of BOA formation via hASH1-induced suppression of the apoptotic pathway. Our study yields a promising new preclinical tool for chemoprevention of peripheral lung carcinomas.

    更新日期:2019-11-01
  • Accurate quantification of dystrophin mRNA and exon skipping levels in duchenne muscular dystrophy.
    Lab. Invest. (IF 3.684) Pub Date : 2010-05-12
    Pietro Spitali,Hans Heemskerk,Rolf H A M Vossen,Alessandra Ferlini,Johan T den Dunnen,Peter A C 't Hoen,Annemieke Aartsma-Rus

    Antisense oligonucleotide (AON)-mediated exon skipping aimed at restoring the reading frame is a promising therapeutic approach for Duchenne muscular dystrophy that is currently tested in clinical trials. Numerous AONs have been tested in (patient-derived) cultured muscle cells and the mdx mouse model. The main outcome to measure AON efficiency is usually the exon-skipping percentage, though different groups use different methods to assess these percentages. Here, we compare a series of techniques to quantify exon skipping levels in AON-treated mdx mouse muscle. We compared densitometry of RT-PCR products on ethidium bromide-stained agarose gels, primary and nested RT-PCR followed by bioanalyzer analysis and melting curve analysis. The digital array system (Fluidigm) allows absolute quantification of skipped vs non-skipped transcripts and was used as a reference. Digital array results show that 1 ng of mdx gastrocnemius muscle-derived mRNA contains approximately 1100 dystrophin transcripts and that 665 transcripts are sufficient to determine exon-skipping levels. Quantification using bioanalyzer or densitometric analysis of primary PCR products resulted in values close to those obtained with digital array. The use of the same technique allows comparison between different groups working on exon skipping in the mdx mouse model.

    更新日期:2019-11-01
  • SRC-induced disintegration of adherens junctions of madin-darby canine kidney cells is dependent on endocytosis of cadherin and antagonized by Tiam-1.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Riitta Palovuori,Raija Sormunen,Sinikka Eskelinen

    The effects of Src tyrosine kinase activation in subconfluent temperature sensitive (ts)-Src-transformed Madin-Darby canine kidney (MDCK) cells were analyzed by shifting them from nonpermissive (40.5 degrees C) to permissive (35 degrees C) temperature. Already, in 15 minutes, adherens junction components were released from the lateral walls and accumulated to basal surfaces. Simultaneously, membranous actin staining vanished, actin bundles appeared at the basal surface, and the cells flattened. The only component phosphorylated and translocated after the shift to 35 degrees C was p120ctn. The epithelial-mesenchymal transition could be inhibited by a specific inhibitor of Src kinase, PP2, or by inhibiting endocytosis. Therefore, Src activation was responsible for the transition, but not because of phosphorylation of adherens junction components but by way of activation of endocytic machinery and RhoGTPase. Expression of an RacGEF, Tiam-1 (T-lymphoma invasion and metastasis gene 1), prevented flattening of Src-transformed MDCK cells at 35 degrees C and resulted in accumulation of cadherin to lateral membranes. In the case where the Src-MDCK cells were cultivated at 35 degrees C and shifted for short time periods to 40.5 degrees C, cadherin rapidly returned to lateral membranes, whereas actin and p120ctn followed hours afterward. This further supports the view that cadherin internalization is the primary target of Src kinase. We also looked at the cell morphology and distribution of cadherin and Tiam-1 in cells grown in three-dimensional gels composed of collagen and laminin or in Matrigel. At nonpermissive temperature, both Src-MDCK and Tiam-1-transfected Src-MDCK cells exhibited nonpolarized morphology in collagen I, a loose cluster in the mixture of collagen I and laminin, and a differentiated cyst in Matrigel. In growth factor-depleted Matrigel, the Src-MDCK cells grew in nondifferentiated clusters, whereas Tiam-1-transfected cells went to apoptosis. The differentiated phenotype of both cell lines could be rescued by Matrigel-conditioned medium, platelet-derived growth factor, or cholera toxin. Concomitantly, both cadherin and Tiam-1 were recruited to lateral membranes. Therefore, cadherin and Tiam-1 seem to be the key players in the differentiation process of MDCK cells.

    更新日期:2019-11-01
  • Matrix metalloproteinase-21 is expressed epithelially during development and in cancer and is up-regulated by transforming growth factor-beta1 in keratinocytes.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Katja Ahokas,Jouko Lohi,Sara A Illman,Elena Llano,Outi Elomaa,Ulla Impola,Marja-Liisa Karjalainen-Lindsberg,Ulpu Saarialho-Kere

    Human matrix metalloproteinase-21 (MMP-21), the newest member of the MMP gene family, has been suggested to play an important role in embryogenesis and tumor progression and to be a target of the Wnt, Pax, and Notch signaling pathways. Here we report detection of MMP-21 by RT-PCR in mouse embryos aged 10.5, 12.5, 13.5, and 16.5 days, as well as in various adult murine organs. In both humans and mice, MMP-21 protein was detected in the epithelial cells of developing kidney, intestine, neuroectoderm, and skin but not in normal adult skin using immunohistochemistry with two unrelated antibodies. However, it was present in invasive cancer cells of aggressive subtypes of basal and squamous cell carcinomas, although it was not expressed in skin disorders characterized by mere keratinocyte hyperproliferation. Of several cytokines tested, transforming growth factor-beta1 induced MMP-21 in vitro in HaCaTs and keratinocytes as judged by real-time quantitative TaqMan PCR. Although suprabasal differentiating keratinocytes expressed MMP-21 in developing skin in vivo, MMP-21-positive keratinocytes were detected by immunohistochemistry in both low and high calcium cultures. MMP-21 expression was not up-regulated by ras transformation in HaCaT cell lines (HaCaT, A5, II-4, and RT3); in skin and colon cancers, its expression did not associate with apoptosis, beta-catenin transactivation, or epithelial MMPs-9 and -10. However, MMP-21 protein was found in the same regions as MMP-7 but not in the same cells. Our results suggest that during development, MMP-21 expression is temporally and spatially tightly controlled. Unlike many classical MMPs, it is present in various normal adult tissues. Among epithelial MMPs, MMP-21 has a unique expression pattern in cancer.

    更新日期:2019-11-01
  • VEGF(121) and VEGF(165) regulate blood vessel diameter through vascular endothelial growth factor receptor 2 in an in vitro angiogenesis model.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Martin N Nakatsu,Richard C A Sainson,Sofía Pérez-del-Pulgar,Jason N Aoto,Mark Aitkenhead,Kevin L Taylor,Philip M Carpenter,Christopher C W Hughes

    Vascular endothelial growth factor (VEGF) is essential for the induction of angiogenesis and drives both endothelial cell (EC) proliferation and migration. It has been suggested that VEGF also regulates vessel diameter, although this has not been tested explicitly. The two most abundant isoforms, VEGF(121) and VEGF(165), both signal through VEGF receptor 2 (VEGFR-2). We recently optimized a three-dimensional in vitro angiogenesis assay using HUVECs growing on Cytodex beads and embedded in fibrin gels. Fibroblasts provide critical factors that promote sprouting, lumen formation, and vessel stability. Using this assay, we have examined the role of VEGF in setting vessel diameter. Low concentrations of both VEGF(121) and VEGF(165) promote growth of long, thin vessels, whereas higher concentrations of VEGF remarkably enhance vessel diameter. Placental growth factor, which binds to VEGFR-1 but not VEGFR-2, does not promote capillary sprouting. Moreover, specific inhibition of VEGFR-2 signaling results in a dramatic reduction of EC sprouting in response to VEGF, indicating the critical importance of this receptor. The increase in vessel diameter is the result of cell proliferation and migration, rather than cellular hypertrophy, and likely depends on MEK1-ERK1/2 signaling. Both phosphatidylinositol 3-kinase and p38 activity are required for cell survival. We conclude that the diameter of new capillary sprouts can be determined by the local concentration of VEGF and that the action of VEGF on angiogenic EC in this assay is critically dependent on signaling through VEGFR-2.

    更新日期:2019-11-01
  • Loss of heterozygosity and mutational analyses of the ACTRII gene locus in human colorectal tumors.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Andreea Olaru,Yuriko Mori,Jing Yin,Suna Wang,Martha C Kimos,Kellie Perry,Yan Xu,Fumiaki Sato,Florin M Selaru,Elena Deacu,Anca Sterian,David Shibata,John M Abraham,Stephen J Meltzer

    The activin type II receptorgene (ACTRII) is mutated in 58.1% of microsatellite-unstable (MSI-H) colorectal cancers and is a close relative of the TGFbeta-1 type II receptor, which is known to be involved in both MSI-H and non-MSI-H colorectal carcinogenesis. We therefore sought to determine whether ACTRII was involved in non-MSI-H colorectal cancers. We evaluated ACTRII inactivation by allelic deletion, loss of mRNA expression, or somatic mutation in 51 non-MSI-H colon cancers. Loss of heterozygosity (LOH) at the ACTRII locus (2q23.1) was found in 9 (17.6%) of 51 primary tumors. Loss of ACTRII mRNA expression was seen in one (14.3%) of the seven LOH-positive primary tumors from which total RNA was available. We also performed DNA sequencing analysis of tumors showing LOH. One LOH-positive primary tumor exhibited a novel germline missense sequence alteration (amino acid substitution, 117 Ile to Phe) that was not found in 23 additional normal individuals, implying that this alteration is not a frequent polymorphism. We conclude that ACTRII is probably involved in both non-MSI-H and MSI-H colorectal carcinogenesis, but more frequently in the latter subgroup.

    更新日期:2019-11-01
  • APC haploinsufficiency, but not CTNNB1 or CDH1 gene mutations, accounts for a fraction of familial adenomatous polyposis patients without APC truncating mutations.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Tiziana Venesio,Antonella Balsamo,Marco Rondo-Spaudo,Liliana Varesco,Mauro Risio,Guglielmina Nadia Ranzani

    Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the development of hundreds to thousands of colorectal adenomatous polyps. In addition to the classic form, there is also attenuated polyposis (attenuated adenomatous polyposis coli; AAPC), which is characterized by a milder phenotype. FAP/AAPC is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Very recently, germline mutations in the base-excision repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas in a subset of patients. APC pathogenic alterations are mostly (>95%) represented by frameshift or nonsense mutations leading to the synthesis of a truncated protein. We identified 20 APC truncating mutation carriers out of 30 FAP/AAPC patients from different Italian kindreds. In the remaining 10 patients, we searched for alterations other than truncating mutations by enzymatic mutation detection, real-time quantitative RT-PCR, and genotyping of polymorphic markers encompassing the APC locus. Moreover, to assess whether mutations of genes interacting with APC can substitute or act in association with APC alterations, we sequenced both CTNNB1 (beta-catenin) and CDH1 (E-cadherin) genes. No CTNNB1 or CDH1 mutations were found. On the contrary, four patients showed a reduced APC gene expression compared with healthy subjects. In three of the four cases, genotyping results were compatible with a constitutive allelic deletion. In one case this conclusion was confirmed by haplotype segregation analysis. Our results support the notion that FAP/AAPC can result from APC constitutive haploinsufficiency, with gene deletion being a possible cause of reduced gene expression.

    更新日期:2019-11-01
  • Activated proliferation of B-cell lymphomas/leukemias with the SHP1 gene silencing by aberrant CpG methylation.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Maho Koyama,Takashi Oka,Mamoru Ouchida,Yoko Nakatani,Ritsuo Nishiuchi,Tadashi Yoshino,Kazuhiko Hayashi,Tadaatsu Akagi,Yoshiki Seino

    Previously we showed reduced protein and mRNA expression of the SHP1 gene in lymphoma/leukemia cell lines and patient specimens by Northern blot, RT-PCR, Western blot, and immunohistochemical analyses. In this study, aberrant methylation in the SHP1 gene promoter was detected in many B-cell leukemia/lymphoma cell lines as well as in patient specimens, including diffuse large B-cell lymphoma (methylation frequency 93%), MALT lymphoma (82%), mantle cell lymphoma (75%), plasmacytoma (100%) and follicular lymphoma (96%) by methylation-specific PCR, bisulfite sequencing, and restriction enzyme-mediated PCR analyses. The methylation frequency was significantly higher in high-grade MALT lymphoma cases (100%) than in low-grade MALT lymphoma cases (70%), which correlated well with the frequency of no expression of SHP1 protein in high-grade (80%) and low-grade MALT lymphoma (54%). It suggests that the SHP1 gene silencing with aberrant CpG methylation relates to the lymphoma progression. SHP1 protein expression was recovered in B-cell lines after the treatment of the demethylating reagent: 5-aza-2'-deoxycytidine. Transfection of the intact SHP1 gene to the hematopoietic cultured cells, which show no expression of the SHP1 gene, induced growth inhibition, indicating that gene silencing of the SHP1 gene by aberrant methylation plays an important role to get the growth advantage of the malignant lymphoma/leukemia cells. The extraordinarily high frequency (75 to 100%) of CpG methylation of the SHP1 gene in B-cell lymphoma/leukemia patient specimens indicates that the SHP1 gene silencing is one of the critical events to the onset of malignant lymphomas/leukemias as well as important implications for the diagnostic or prognostic markers and the target of gene therapy. These data support the possibility that the SHP1 gene is one of the tumor suppressor genes.

    更新日期:2019-11-01
  • Programmed cell death in rheumatoid arthritis peripheral blood T-cell subpopulations determined by laser scanning cytometry.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Peter Szodoray,Stig Jellestad,Britt Nakken,Johan G Brun,Roland Jonsson

    Because peripheral blood mononuclear cells play an important role in the perpetuation of the autoimmune process in rheumatoid arthritis (RA) and because the maintenance of these cells might be caused by the dysregulation of apoptosis, we investigated the apoptosis susceptibility of peripheral blood mononuclear cells from patients with RA. Freshly separated peripheral blood lymphocytes were stained for apoptosis markers (CD95, Bax, Bcl-2, TNF receptor) and for an activation marker (CD45-RO), and the apoptosis frequency of cells bearing these markers were assessed by the terminal-deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling method and nuclear condensation analysis with laser scanning cytometry. Also, the ability of CD4(+) and CD8(+) T-cell populations to undergo apoptosis was investigated with 24-hour culture in medium alone or with different apoptosis inducers (anti-CD3, anti-CD95, anti-TNF receptor). Laser scanning cytometry analysis was used to enumerate the phenotype and apoptosis ratios of both freshly isolated and cultured lymphocytes. Quantitative ELISA was performed to detect plasma levels of TNF-alpha and soluble Fas ligand. Furthermore, we studied the relationship between marked apoptotic defects in patients with RA and the severity of clinical disease. CD4(+) T-cell counts in patients with RA were elevated compared with controls. A decreased rate of anti-CD95-mediated apoptosis was found within the CD4(+) and CD8(+) lymphocytic subpopulations. In patients with RA, decreased Bax expression and decreased apoptosis rate within the Bax-positive cells were found, whereas Bcl-2 expression was elevated. The CD45-RO expression was higher, whereas the apoptosis within CD45-RO(+) cells were decreased in RA. Evaluation of plasma soluble Fas ligand revealed significantly decreased levels in patients compared with controls. The reduced susceptibility to CD95-mediated apoptosis may contribute to the expansion of an activated CD4(+) lymphocyte subpopulation and thus to the maintenance of peripheral autoreactive T-cell clones in RA. We also revealed a relationship between in vitro demonstrated lymphocyte apoptosis defects and clinical disease activity.

    更新日期:2019-11-01
  • Transcription of sonic hedgehog, a potential factor for gastric morphogenesis and gastric mucosa maintenance, is up-regulated in acidic conditions.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Arno Dimmler,Thomas Brabletz,Falk Hlubek,Manuela Häfner,Tilman Rau,Thomas Kirchner,Gerhard Faller

    Gastric body mucosa atrophy predisposes one to gastric cancer. Disturbances in the gastric differentiation process might play a role in the evolution of gastric atrophy. Sonic hedgehog (Shh) has recently been implicated as a crucial factor in gastric organogenesis and gland differentiation. In this study we investigated the expression of key factors in the Shh pathway, namely Shh and its receptor Patched (Ptc), in normal and pathologic stomach mucosa. Furthermore, the potential role of pH for Shh dysregulation was analyzed. Ten gastric biopsy specimens each from normal gastric mucosa, chronic nonatrophic gastritis, atrophic gastritis, and gastric cancer were included. Expression of Shh and Ptc was analyzed by immunohistochemistry. In normal body mucosa and in nonatrophic body gastritis, Shh was strongly expressed in parietal cells. Ptc was also expressed in gastric chief cells. Shh expression was almost completely lost in atrophic gastritis and in gastric cancer and absent in intestinal metaplasia. Ptc was markedly reduced in atrophy and only weakly positive in intestinal metaplasia and gastric cancer. In in vitro experiments, gastric cancer cell line 23132 was found positive for Shh. In long-term culture as well as in culture conditions with low pH, transcription of Shh in 23132 was significantly increased in quantitative reverse transcription PCR analyses. We concluded that the decreased expression of the Shh pathway in atrophic gastritis and gastric cancer might reflect altered differentiation processes within the gastric unit and contributes to the development of gastric atrophy. The increase of gastric pH might play a role in the development of gastric mucosa atrophy via reduction of Shh transcription.

    更新日期:2019-11-01
  • A novel in vitro model of trophoblast-mediated decidual blood vessel remodeling.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Caroline Dunk,Ljiljana Petkovic,Dora Baczyk,Janet Rossant,Elke Winterhager,Stephen Lye

    In vivo the extravillous trophoblasts (EVTs) penetrate the decidua and the first third of the myometrium to remodel the uterine spiral arteries and achieve the high-flow, low-resistance circulation characteristic of the intervillous space of the term placenta. Much of our understanding of these processes comes from histologic analysis of placental bed biopsies, a limited tissue source and one that can provide only a snapshot of a dynamic process. To better characterize these cellular interactions, we have developed an in vitro co-culture system in which first trimester villous explants are cultured at low oxygen tension in contact with 2-mm(2) sections of decidua parietalis from the same patient. Hematoxylin eosin counterstaining of paraffin sections shows that EVT columns form at the tips of the placental villi and adhere and penetrate the decidual surface. The decidual blood vessels in the path of the EVT show morphologic disruption. Immunohistochemical analysis of the co-cultures using both an endothelial specific anti-CD31 and an anti-smooth muscle actin antibody show a disruption of the integrity of the vessel lining together with a complete loss of organized smooth muscle actin surrounding the blood vessels. In contrast control decidua samples in the absence of placental villi exhibit blood vessels with a complete endothelial lining and an organized muscular sheath. Using both an anti-cytokeratin-7 and anti-Cdx-2 antibody specific to trophoblasts, we show that these changes coincide with invasion of the vessels by endovascular trophoblasts and penetration of the decidua by interstitial EVTs. No EVTs were found in the control decidua. Thus we conclude that this in vitro model mimics the physiologic change observed in vivo during trophoblast invasion into maternal decidual tissues, and as such it may provide useful information concerning the interactions between EVTs and decidual cells and vessels during early gestation.

    更新日期:2019-11-01
  • Human embryonic stem cells as an in vitro model for human vascular development and the induction of vascular differentiation.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Sharon Gerecht-Nir,Anna Ziskind,Smadar Cohen,Joseph Itskovitz-Eldor

    Early embryonic blood vessels are typically composed of fragile tubes of endothelial cells encircled by vascular smooth muscle cells. Early human vasculogenesis was explored in spontaneous and directed differentiation models derived from human embryonic stem (HES) cells. In a 3-dimensional (3D) model, HES cells were studied for their potential for vascular differentiation during the spontaneous formation of embryoid bodies. Directed differentiation was investigated by means of a 2-dimensional (2D) differentiation method to promote vascular differentiation from HES cells (without the formation of embryoid bodies). Using this latter approach, up-regulation of early lineage markers of endothelial progenitors were induced. Additional culture under strict conditions and exposure to angiogenic growth factors resulted in a prolonged differentiation pathway into mature endothelial cells and up-regulation of vascular smooth muscle cell markers. The use of 3D collagen gels and Matrigel assays for the induction and inhibition of human vascular sprouting in vitro further established the vascular potential of the cells generated by the 2D differentiation system. Our study shows that HES cells can provide useful models to study early differentiation and development of blood vessels. Moreover, the 2D differentiation model facilitates both the production of vascular lineage cells from HES cells for various potential therapeutic applications and also provides a model for studying the mechanisms involved in early human embryonic blood vessel development.

    更新日期:2019-11-01
  • Expression of placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in human normal and malignant invasive trophoblastic cells.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Kazuhiko Ino,Fumitaka Kikkawa,Takahiro Suzuki,Hiroaki Kajiyama,Kiyosumi Shibata,Seiji Nomura,Atsuo Itakura,Mitsuaki Ito,Tetsuro Nagasaka,Akira Hattori,Masafumi Tsujimoto,Shigehiko Mizutani

    We recently identified two novel aminopeptidases, placental leucine aminopeptidase (P-LAP) and adipocyte-derived leucine aminopeptidase (A-LAP). Enzymatically, P-LAP degrades oxytocin, vasopressin, and angiotensin III, while A-LAP degrades angiotensin II and kallidin. In this study we investigated the expression and localization of P-LAP and A-LAP in human trophoblastic cells in the normal placenta (n = 26), gestational choriocarcinoma (n = 8), and placental site trophoblastic tumor (n = 3). On immunoblot analysis both P-LAP and A-LAP proteins were detected in normal placenta and five choriocarcinoma tissues, as well as in two choriocarcinoma cell lines. Immunohistochemical staining of normal placental tissues demonstrated that P-LAP was not only localized in villous syncytiotrophoblasts but also highly expressed in extravillous trophoblasts (EVTs) invading the decidua or maternal spiral arteries. The expression level of P-LAP on these invasive EVTs reached a maximum during the late first to second trimesters of pregnancy, and it decreased in the third trimester. Similarly, A-LAP was strongly expressed in EVTs invading the decidua or spiral arteries in the second trimester of pregnancy, while it was weakly or moderately expressed in villous cytotrophoblasts or EVTs located in the cell columns. These two aminopeptidases were more strongly expressed in all eight choriocarcinomas and three placental site trophoblastic tumors and mainly localized to the intermediate-type trophoblastic tumor cells invading the uterine myometrium or stromal vessels. In summary P-LAP and A-LAP were predominantly expressed in the invasive phenotype of EVTs during placentation, as well as in the invasive tumor cells of trophoblastic neoplasms. These results suggest the involvement of these aminopeptidases in invasiveness of both normal and malignant intermediate-type trophoblasts possibly through degradation of specific peptide substrates.

    更新日期:2019-11-01
  • Induction of intercellular adhesion molecule-1 on human brain endothelial cells by HIV-1 gp120: role of CD4 and chemokine coreceptors.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Monique F Stins,Donna Pearce,Francescopaolo Di Cello,Anat Erdreich-Epstein,Carlos A Pardo,Kwang Sik Kim

    Central nervous system dysfunction is commonly observed in children with HIV-1 infection, but the mechanisms whereby HIV-1 causes encephalopathy are not completely understood. We have previously shown that human brain microvascular endothelial cells (HBMEC) from children are responsive to gp120 derived from X4 HIV-1 by increasing expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1. However, the mechanisms involved in gp120-mediated up-regulation of cell adhesion molecule expression is unclear. In the present study, we found that gp120 derived from both X4 and R5 HIV-1 induced increased expression of ICAM-1 on HBMEC, but the degree of this up-regulation differed among the various HBMEC isolates. The up-regulation of ICAM-1 was inhibited by anti-CD4 antibodies as well as by specific antibodies directed against chemokine receptors and small-molecule coreceptor inhibitors. Anti-CD4 antibodies inhibited the increase in ICAM-1 expression mediated by gp120 derived from X4 and R5 HIV-1, whereas antibodies against chemokine receptors displayed a differential inhibition depending on the source of gp120. Both X4 and R5 gp120-induced ICAM-1 expression was sensitive to pertussis toxin and involved the nuclear factor-kB pathway. These findings indicate a direct involvement of CD4 and a differential involvement of chemokine receptors in the activation of pediatric HBMEC by X4 and R5 gp120. The activation of brain endothelium of children by HIV-1 protein gp120 by way of CD4 and chemokine receptors may have implications for the pathogenesis of HIV-1 encephalopathy in the pediatric population.

    更新日期:2019-11-01
  • Effects of Helicobacter pylori infection on the link between regenerating gene expression and serum gastrin levels in Mongolian gerbils.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Hirokazu Fukui,Francesco Franceschi,Rebecca L Penland,Taro Sakai,Antonia R Sepulveda,Takahiro Fujimori,Akira Terano,Tsutomu Chiba,Robert M Genta

    Although regenerating gene (Reg) protein is reported to have a trophic effect on gastric epithelial cells, its involvement in human gastric diseases is not clear. We have recently shown that both gastrin and gastric mucosal inflammation enhance Reg gene expression in the fundic mucosa in rats. This study was designed to clarify whether Reg protein is involved in Helicobacter pylori-induced gastritis and whether Reg gene expression is linked to serum gastrin levels in this condition. Mongolian gerbils were inoculated with an H. pylori strain isolated from a gastric cancer patient. Four weeks later, some of the gerbils with H. pylori infection were eradicated by lansoprazole, amoxicillin, and clarithromycin. The time courses of changes in Reg gene expression, serum gastrin levels, gastric acidity, and histopathologic factors were examined. Four weeks after H. pylori infection, gastritis started spreading to the fundic mucosa, and gastric acidity started reducing. Serum gastrin levels and Reg mRNA expression in the fundus were significantly increased 6 weeks after infection. Reg mRNA expression in the fundus correlated significantly with both serum gastrin levels and the severity of fundic mucosal inflammation. After H. pylori eradication, serum gastrin levels and fundic mucosal inflammation were normalized, and the increase in Reg mRNA expression was abolished. The Reg gene is associated with hypergastrinemia and fundic mucosal inflammation and may be involved in H. pylori-induced gastritis.

    更新日期:2019-11-01
  • Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Anette Weber,Ulrich R Hengge,Doris Urbanik,Annett Markwart,Alireza Mirmohammadsaegh,Martin B Reichel,Christian Wittekind,Peter Wiedemann,Andrea Tannapfel

    The v-raf murine sarcoma viral homolog B1 (BRAF) gene, one of the human isoforms of RAF, is activated by Ras, leading to cooperative effects in cells responsive to growth factor signals. Recently, somatic missense mutations of the BRAF gene have been detected in more than 66% of malignant melanomas of the skin. We analyzed 42 malignant melanomas of the uvea, 3 corresponding liver metastases, and 10 cutaneous melanomas for possible BRAF mutations: after microdissection, mutation analysis of BRAF and KRAS was performed. The expression of extracellular-regulated kinase 1 and 2 (ERK1/2), an important downstream point of convergence in the Ras-RAF-MEK-Erk pathway, was analyzed immunohistochemically. Interestingly, we failed to detect activating BRAF mutations in uvea melanomas and their corresponding liver metastases. There were no mutations of BRAF in corresponding non-neoplastic uvea specimens, although we detected three BRAF mutations in sporadic cutaneous melanoma that led to a substitution of valine by glutamic acid at position 599 (V599E). KRAS mutations were detected in 1 of 10 cutaneous melanoma but not in uveal or metastatic melanoma. Despite the lack of activating mutations in the BRAF gene, we identified constitutively activated ERK in almost all (86%) uveal melanoma tissues tested but not in corresponding normal retina or uveal cells. Our data indicate that BRAF gene mutations are rare to absent events in uveal melanoma. The finding of activated Erk suggests a causative role for MAPK activation in uveal melanoma independent of activating BRAF or RAS mutations.

    更新日期:2019-11-01
  • Specific MAP-kinase blockade protects against renal damage in homozygous TGR(mRen2)27 rats.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Martin H de Borst,Gerjan Navis,Rudolf A de Boer,Sippie Huitema,Lotte M Vis,Wiek H van Gilst,Harry van Goor

    Angiotensin II (AngII) plays an important role in renal damage by acting on hemodynamics, cell-growth, proliferation, and fibrosis, mainly by effects on the AngII type 1 (AT(1)) receptor. The AT(1) receptor activates several intracellular signaling molecules such as mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, but their role in AngII-mediated renal damage is not well characterized. We therefore investigated whether pharmacologic blockade of ERK and p38 could prevent renal damage in high-renin homozygous transgenic rats (Ren2), with the effects of an AT(1) receptor antagonist (AT(1)-RA) as a reference. Seven-week-old homozygous Ren2 rats were treated with low-dose AT(1)-RA candesartan, ERK inhibitor tyrphostin, or p38 inhibitor SB239063 for 4 weeks. Untreated Ren2 and SD rats served as controls. Blood pressure was measured at 7 and 11 weeks. At 11 weeks, plasma renin activity (PRA) and serum aldosterone were determined, and the animals were killed. Kidney sections were scored for glomerular and interstitial smooth muscle actin and glomerular desmin expression as early markers for renal damage. Mesangial matrix expansion was determined as a marker for structural damage. PRA and aldosterone levels were elevated in untreated Ren2 rats in comparison to SD controls. AT(1)-RA further increased PRA but decreased aldosterone. All parameters of renal damage were elevated in untreated Ren2 rats. Blood pressure was not elevated at week 7 in Ren2 and not affected by either treatment. Mild signs of hypertensive damage were found in untreated Ren2 rats. All interventions significantly diminished damage to glomerular epithelium and interstitium. In addition, AT(1) receptor and p38 blockade reduced mesangial matrix expansion. In homozygous Ren2 rats, renal damage was ameliorated by a nonhypotensive dose of an AT(1)-RA and, similarly, by blockade of ERK or p38. This suggests that ERK and p38 are involved in AngII-mediated renal damage.

    更新日期:2019-11-01
  • A novel tool for detecting amyloid deposits in systemic amyloidosis in vitro and in vivo.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Yukio Ando,Katsuki Haraoka,Hisayasu Terazaki,Yutaka Tanoue,Kensuke Ishikawa,Shoichi Katsuragi,Masaaki Nakamura,Xuguo Sun,Kazuko Nakagawa,Kazumi Sasamoto,Kazuhiro Takesako,Takashi Ishizaki,Yutaka Sasaki,Katsumi Doh-ura

    We synthesized (trans,trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB) and used this compound to detect amyloid fibrils in autopsy and biopsy samples from patients with localized amyloidosis, such as familial prion disease, and systemic amyloidosis, such as familial amyloidotic polyneuropathy, amyloid A (AA) amyloidosis, light chain (AL) amyloidosis, and dialysis-related amyloidosis. BSB showed reactions in all Congo red-positive and immunoreactive regions of the samples examined in the study, and some amyloid fibrils in the tissues could be detected more precisely with BSB than with the other methods. In the mouse model of AA amyloidosis, injected BSB reacted with amyloid in all regions in the serial sections in which Congo red staining was positive. A highly sensitive 27-MHz quartz crystal microbalance analysis revealed that BSB showed a significant affinity for amyloid fibrils purified from familial amyloidotic polyneuropathy and dialysis-related amyloidosis samples and suppressed formation of transthyretin amyloid in vitro. These results suggest that BSB may become a valuable tool for detection of amyloid deposits in amyloidosis and of the mechanism of amyloid formation.

    更新日期:2019-11-01
  • TNF-independent development of transient anemia of chronic disease in a mouse model of protracted septic peritonitis.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Thomas Schubert,Bernd Echtenacher,Ferdinand Hofstädter,Daniela N Männel

    TNF is considered one of the inflammatory cytokines and contributes mainly to the generation of anemia of chronic disease (ACD). In nude mice TNF has been reported to impair iron metabolism and erythropoiesis, leading to anemia with a low serum iron and preserved iron stores. In this work, we established a murine model for ACD based on sublethal cecal ligation and puncture (CLP) with ensuing protracted peritonitis. Starting on Day 3 after CLP, a severe protracted depression of erythropoiesis in the bone marrow was noted. Two weeks after CLP, we observed a moderate normochromic anemia, low serum iron concentration, and preserved iron stores consistent with transient ACD. To determine whether TNF contributes to the development of ACD in vivo, we neutralized TNF after CLP shortly before and during the phase of most severe bone marrow depression to prevent anemia. Additionally, we studied TNF-deficient mice undergoing CLP. Two weeks after CLP, we determined red blood count, hemoglobin concentration, hematocrit, serum iron concentration, and iron stores in spleens of wild-type mice, TNF-deficient mice, and mice after neutralization of TNF. Neutralization of TNF after CLP could not prevent mice from contracting anemia. Accordingly, TNF-deficient mice developed anemia to the same extent as wild-type mice. Serum iron concentration was lowered and iron stores were overloaded in both TNF-deficient and wild-type mice after CLP. Our results clearly demonstrate that TNF is not a mediator of ACD in our model with transient anemia induced by protracted septic peritonitis.

    更新日期:2019-11-01
  • Differences in the involvement of prostanoids from Kupffer cells in the mediation of anaphylatoxin C5a-, zymosan-, and lipopolysaccharide-dependent hepatic glucose output and flow reduction.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Sabine Pestel,Gerald Schlaf,Otto Götze,Kurt Jungermann,Henrike L Schieferdecker

    Various inflammatory stimuli such as anaphylatoxin C5a, zymosan, and lipopolysaccharides (LPSs) have been reported both to enhance glucose output in the perfused rat liver and to induce prostanoid (ie, prostaglandin and thromboxane) release from Kupffer cells, the resident liver macrophages. Because prostanoids can enhance glucose output from hepatocytes, it was the aim of this study to compare the possible roles of prostanoids released after C5a, zymosan, and LPS in the mediation of hepatic glucose output. In perfused livers both C5a and zymosan immediately enhanced glucose output, reduced flow, and induced prostanoid overflow into the hepatic vein, but with different quantities and kinetics. Only the C5a-induced but not the zymosan-induced effects were abrogated by inhibitors of prostanoid signaling as the prostanoid synthesis inhibitor indomethacin and the thromboxane receptor antagonist daltroban. In contrast to C5a and zymosan, LPS had no effect on glucose output, flow rate, or prostanoid overflow. In isolated Kupffer cells, C5a and zymosan induced maximal release of prostaglandins D(2) and E(2) and of thromboxane A(2) within a period of 0 to 2 minutes and 5 to 15 minutes, respectively. In pulse-chase experiments, maximal prostanoid release was already observed after 2 minutes of continuous stimulation with C5a, but only after 10 to 15 minutes of continuous stimulation with zymosan. LPS-dependent prostanoid release was not seen before 1 hour. Thus, even though C5a, zymosan, and LPS induced prostanoid release from Kupffer cells, only C5a quickly regulated hepatic glucose metabolism in a prostanoid-dependent manner (due to the kinetics and quantities of prostanoids released).

    更新日期:2019-11-01
  • Attenuated cerulein-induced pancreatitis in nuclear factor-kappaB-deficient mice.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Domenica Altavilla,Ciro Famulari,Maria Passaniti,Mariarosaria Galeano,Antonio Macrì,Paolo Seminara,Letteria Minutoli,Herbert Marini,Margherita Calò,Francesco S Venuti,Maria Esposito,Francesco Squadrito

    Nuclear factor (NF)-kappaB plays a central role in acute pancreatitis. We studied cerulein (CER)-induced pancreatitis in NF-kappaB knockout (KO) mice. NF-kappaB KO mice and normal control littermate wild-type (WT) mice were given four hyperstimulating doses of cerulein every hour to elicit secreatagogue-induced pancreatitis. Malonildialdehyde activity, glutathione levels, myeloperoxidase activity, TNF-alpha, and NF-kappaB binding activity and its inhibitory protein IkappaBalpha were studied in the pancreas. Furthermore, we measured plasma lipase and amylase and the histological damage. KO mice had reduced malonildialdehyde levels (WT + CER = 4.083 +/- 0.95 micromol/g; KO + CER = 1.513 +/- 0.63 microol/g), decreased myeloperoxidase activity (WT + CER = 19.3 +/- 2.39 mU/g; KO + CER = 10.21 +/- 2.05 mU/g), increased glutathione levels (WT + CER 6.22 +/- 2.46 micromol/g; KO + CER = 15. 516 +/- 2.92 micromol/g), and reduced serum levels of amylase (WT + CER = 2519 +/- 656.9 U/L; KO + CER = 916 +/- 280.4 U/L) and lipase (WT + CER = 1420 +/- 170 U/L; KO + CER = 861 +/- 172. 3 U/L). KO mice showed reduced pancreatic NF-kappaB activation, decreased TNF-alpha tissue content, and reduced histologic alterations. Our data suggest that KO mice have an attenuated cerulein-induced pancreatitis and help to define the possible interaction between NF-kappaB activation and oxidative stress in this deleterious event.

    更新日期:2019-11-01
  • Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates myocardial ischemia/reperfusion injury in a rat model.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    Haruyasu Ito,Atsushi Nakano,Makoto Kinoshita,Akira Matsumori

    Thiazolidinediones are insulin-sensitizing drugs, ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which play an important role in the modulation of inflammatory responses. Myocardial ischemia/reperfusion (MI/R) injury is associated with inflammation, in which various cells, particularly monocytes and macrophages, are involved. This study examined the effects of the thiazolidinedione peroxisome proliferator-activated receptor-gamma ligand, pioglitazone, in a rat model of MI/R injury. Pioglitazone at 3 mg/kg/day or the vehicle was administered for 7 days before rats were subjected to 30 minutes of coronary ligation followed by 24 hours of reperfusion. The mRNA expression [monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1] in the ischemic region, the number of infiltrating macrophages in the ischemic region, and the myocardial infarct size were examined. The inhibitory effects of pioglitazone on activated macrophages were studied in vitro. Phorbol 12-myristate 13-acetate-induced MCP-1 production, in the absence or presence of pioglitazone, were assayed in cultured macrophages. Compared with the control group, (1). mRNA levels of MCP-1 and intercellular adhesion molecule-1 and the number of infiltrating macrophages in the ischemic region were significantly lower in the pioglitazone-treated group; and (2). myocardial infarct size was significantly smaller in the pioglitazone-treated group. Phorbol 12-myristate 13-acetate-stimulated cultured macrophages in the presence of pioglitazone produced significantly lower levels of MCP-1 than the stimulated control in the absence of pioglitazone. These observations demonstrate that pioglitazone has anti-inflammatory effects in MI/R injury that are independent of its insulin-sensitizing effect.

    更新日期:2019-11-01
  • Androgen receptor mutations in high-grade prostate cancer before hormonal therapy.
    Lab. Invest. (IF 3.684) Pub Date : 2003-12-24
    James Thompson,Eija-Riitta Hyytinen,Kyllikki Haapala,Immo Rantala,Heikki J Helin,Olli A Jänne,Jorma J Palvimo,Pasi A Koivisto

    Androgen action is mediated through androgen receptor (AR), which appears to undergo structural and functional alterations during prostate cancer (CaP) progression. AR mutations have been infrequently reported in CaP before hormonal therapy, but in untreated, advanced tumors AR mutations are suggested to be more common. To investigate the frequency of AR mutations in aggressive CaP before hormonal therapy, we have analyzed AR coding region for aberrations in 21 paraffin-embedded prostate carcinoma samples (14 primary tumors, 7 metastases) of poor histologic differentiation. Single-stranded conformational polymorphism and sequencing analyses revealed AR missense mutations in 29% (4/14) of the primary tumors and in one (14%) metastasis. Mutations resided in the transactivation domain and in the hinge region. One of the hinge region mutants, Ser646Phe, that was identified in a patient with short endocrine therapy response, exhibited a markedly increased transcriptional activity on single androgen response element-containing promoters. In conclusion, AR mutations are frequent in high-grade CaP before initiation of hormonal therapy, and these mutations may play a role in poor therapy response and emergence of hormone-refractory CaP in some cases.

    更新日期:2019-11-01
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